The identification of host genetic factors provides a valuable tool for the identification of host cellular components that are operative in pathways leading to disease. Even genetic factors with small relative or attributable risks may be important since they suggest proteins and pathways that may provide targets for therapeutic intervention. However, the discovery of genes underpinning complex diseases requires large numbers of affected and unaffected cases and controls. Milestones reached this fiscal year include the completion of enrollment of 4000 participants for an investigation of the genetic correlates of Epstein-Barr-related nasal pharyngeal carcinoma in a high prevalence population and 2200 persons with hepatitis B virus infection, both in China.The genetic modifying roles of several genes involved in innate immunity in HIV-1 infection and pathogenesis was identified in our group using over 3000 HIV-1-exposed or infected persons enrolled in 5 natural history cohorts. Trim5 provides innate resistance to cross-species transmission of retroviruses. A polymorphism with functional consequence in the TRIM5 promoter was associated with increased risk of infection. APOBEC3G is an enzyme that hypermutates the nascent HIV DNA pre-integration. However, the antiviral activity of APOBEC3G is suppressed by HIV-1 viral infectivity factor and another human protein, Cullin 5 via a degradation pathway. Variants in the Cul5 gene are strongly associated with rapid loss of CD4 T cells. HIV-1 transmission is also influenced by chemokines; genetic variation in chemokines binding the HIV-1 CCR5 co-receptor have also been shown to influence HIV-1 transmission and HIV-1 progression to AIDS. These results strongly suggest that genetic variability explains in part the heterogeneity observed in human populations in susceptibility to HIV-1 infection and pathogenesis and may point to new targets for vaccine and drug development.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010297-09
Application #
7338378
Study Section
(LGD)
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
An, Ping; Thio, Chloe L; Kirk, Gregory D et al. (2008) Regulatory polymorphisms in the interleukin-18 promoter are associated with hepatitis C virus clearance. J Infect Dis 198:1159-65
Li, Xing; Gold, Bert; O'hUigin, Colm et al. (2007) Unique features of TRIM5alpha among closely related human TRIM family members. Virology 360:419-33
Guo, Xiu Chan; Scott, Kevin; Liu, Yan et al. (2006) Genetic factors leading to chronic Epstein-Barr virus infection and nasopharyngeal carcinoma in South East China: study design, methods and feasibility. Hum Genomics 2:365-75
Javanbakht, Hassan; An, Ping; Gold, Bert et al. (2006) Effects of human TRIM5alpha polymorphisms on antiretroviral function and susceptibility to human immunodeficiency virus infection. Virology 354:15-27
Modi, William S; Lautenberger, James; An, Ping et al. (2006) Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression. Am J Hum Genet 79:120-8
Guo, Xiu-Chan; O'Brien, Stephen J; Winkler, Cheryl et al. (2006) [Association study of chromosome 4 STRs polymorphisms with nasopharyngeal carcinoma] Yi Chuan 28:783-90
Walsh, Emily C; Sabeti, Pardis; Hutcheson, Holli B et al. (2006) Searching for signals of evolutionary selection in 168 genes related to immune function. Hum Genet 119:92-102
Song, Byeongwoon; Gold, Bert; O'Huigin, Colm et al. (2005) The B30.2(SPRY) domain of the retroviral restriction factor TRIM5alpha exhibits lineage-specific length and sequence variation in primates. J Virol 79:6111-21
Modi, W S; Scott, K; Goedert, J J et al. (2005) Haplotype analysis of the SDF-1 (CXCL12) gene in a longitudinal HIV-1/AIDS cohort study. Genes Immun 6:691-8
Duggal, Priya; Winkler, Cheryl A; An, Ping et al. (2005) The effect of RANTES chemokine genetic variants on early HIV-1 plasma RNA among African American injection drug users. J Acquir Immune Defic Syndr 38:584-9

Showing the most recent 10 out of 15 publications